Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
  • C07D285/01—Five-membered rings
  • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
  • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
  • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
  • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
  • C07D285/135—Nitrogen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

• the present invention relates to new 1,3,4-thiadiazole derivatives useful as antiulcer agents of the general formula (I): ##STR3## wherein R 1 represents a group of the formula: ##STR4## and R 2 represents an amino, lower alkylamino, cyclohexylamino, benzoylamino, mercapto or lower alkylthio group and a process for producing the same.
• the compounds of the formula (I) are new compounds having an excellent antagonism to histamine H 2 receptors and useful as long lasting inhibitors against secretion of acid in the stomach or antiulcer agents.
• the present invention provides 1,3,4-thiadiazole derivatives of the general formula (I): ##STR5## wherein R 1 represents a group of the formula: ##STR6## and R 2 represents an amino, lower alkylamino, cyclohexylamino, benzoylamino, mercapto or lower alkylthio group and acid-addition salts of them.
• the present invention provides also a process for producing 1,3,4-thiadiazole derivatives of the general formula (I): ##STR7## wherein R 1 and R 2 have the same meaning as above by ring-closing condensation of bithioureas or thiocarbamyl dithiocarbazinic acid esters of the general formula (II): ##STR8## wherein R 1 and R 2 have the same meaning as above.
• the present invention provides an anti-ulcer agent characterized by containing as an active ingredient a 1,3,4-thiadiazole derivative of the general formula (I): ##STR9## wherein R 1 and R 2 have the same meaning as above.
• the present invention relates to new 1,3,4-thiadiazole derivatives useful as antiulcer agents, process for the production thereof and the use thereof.
• the 1,3,4-thiadiazole derivatives have the following general formula: ##STR10## wherein R 1 represents a group of the formula: ##STR11## and R 2 represents an amino, lower alkylamino, cyclohexylamino, benzoylamino, mercapto or lower alkylthio group.
• the lower alkylamino and lower alkylthio groups herein indicate alkylamino and alkylthio groups containing a straight chain or branched alkyl group having about 1 to 4 carbon atoms.
• the lower alkylamino groups include, for example, methylamino, ethylamino, propylamino and t-butylamino groups.
• the lower alkylthio groups include, for example, methylthio, ethylthio, propylthio and butylthio groups.
• a typical process for producing the compounds of the present invention may be represented by the following chemical formula: ##STR13## wherein R 1 and R 2 have the same meaning as above.
• the compounds (I) of the present invention can be produced by ring-closing condensation of starting bithioureas or thiocarbamyl dithiocarbazinic acid esters of the general formula (II):
• the organic solvents usable in the above-mentioned reaction include, for example, ethanol, n-propanol, benzene, toluene, tetrahydrofuran (hereinafter referred to as THF), 1,4-dioxane, pyridine, and dimethylformamide (hereinafter referred to as DMF).
• the condensing agents include, for example, N,N'-dicyclohexylcarbodiimide (hereinafter referred to as DCC), N,N'-carbonyldiimidazole (hereinafter referred to as CDI), diethyl azodicarboxylate/triphenylphosphine and 2,2'-dipyridyl disulfide/triphenylphosphine.
• DCC N,N'-dicyclohexylcarbodiimide
• CDI N,N'-carbonyldiimidazole
• diethyl azodicarboxylate/triphenylphosphine diethyl azodicarboxylate/triphenylphosphine
• 2,2'-dipyridyl disulfide/triphenylphosphine 2,2'-dipyridyl disulfide/triphenylphosphine.
• DCC is particularly preferred.
• the condensing agent is used in an amount of generally 1 to 3 mols per mol of the compound of the formula (II).
• reaction conditions vary depending on the variety of the solvent. Generally, the reaction is carried out preferably at a temperature ranging from room temperature to reflux temperature for 1 to 40 h.
• the compounds (I) of the present invention may be produced by a ring-closing condensation of the starting compound (II) in an organic solvent preferably in the presence of a condensing agent (see Examples 1, 3, 4 and 5).
• the starting compound of the formula (II) is prepared previously.
• the intended compound may be prepared directly by the following series of the reactions including the reaction for the preparation of the starting compound (see Example 6): ##STR14##
• An intended compound (I)' in which R 2 represents --SH group can be obtained from another starting compound of the formula (II) which contains an easily removable group particularly phenylamino group, in place of the substituent R 2 by the ring-closing condensation in an aqueous acid solution in such a manner that the side-reaction is effected preferentially (see Example 2).
• the thus obtained compound (I) of the present invention is a new compound having an excellent antagonism to histamine H 2 receptors and useful as a long lasting inhibitor to secretion of acid in the stomach or antiulcer agent.
• the antiulcer agent of the present invention contains the compound of the above formula (I) or its acid addition salt as the effective ingredient.
• the acid-addition salt may be prepared by an ordinary process.
• the suitable acids for use in the preparation of the acid-addition salts include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid and gluconic acid.
• the antiulcer agent of the present invention may be administered either perorally or parenterally.
• the antiulcer agent When the antiulcer agent is administered perorally, it is formulated generally into tablets, powders, capsules, granules or syrups. When the antiulcer agent is administered parenterally, it is formulated into injections or suppositories.
• the effective ingredient may be mixed with known excipients and adjuvants used generally for the formulation of the preparations such as polyvinyl pyrrolidone, sodium chondroitin sulfate, gelatin, human serum albumin, dextran T-10, calcium gluconate, calcium pantothenate, calcium lactate, ⁇ -cyclodextrin, lactose, starch, magnesium stearate, talc, vegetable oil, carboxymethylcellulose, citric acid, sodium dihydrogenphosphate, mannitol, crystalline cellulose and polyvinyl alcohol to obtain products of various forms.
• excipients and adjuvants used generally for the formulation of the preparations such as polyvinyl pyrrolidone, sodium chondroitin sulfate, gelatin, human serum albumin, dextran T-10, calcium gluconate, calcium pantothenate, calcium lactate, ⁇ -cyclodextrin, lactose, starch, magnesium stearate, talc,
• the effective dose of the antiulcer agent of the present invention is generally 0.1 to 100 mg/kg.
• the dose should be determined by taking various factors, such as the symptoms and age of the patient, administration method, form of the agent and number of times of the administration, into account.
• the compound (I) of the present invention has only a low toxicity allowable as a medicine.
• the acute toxicities of a compound of the formula (I) wherein R 2 represents --NH 2 in mice and rats are as shown in Table 1.
• the acute toxicities of compounds of the formula (I) wherein R 2 represents --NHCH 3 , --SH or --SCH 3 are nearly equal to that shown in Table 1.
• the reaction liquid was concentrated under reduced pressure. The residue was dissolved in chloroform. The resulting solution was washed with 5% acetic acid, 5% aqueous potassium carbonate solution and water successively. The chloroform layer was dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was dissolved in ethanol saturated with hydrogen chloride gas. The solution was left to stand for a while and the solvent was then evaporated off. The residue was dissolved in anhydrous methanol.
• the contraction action of the atrium was measured by means of a strain gauge (TB-612T; a product of Nihon Koden Co.) and the output was determined from a heart rate determined with a tachometer (AT-600 G; a product of Nihon Koden Co.).
• Histamine (used in the form of its dihydrochloride; the same shall apply hereinafter) in a concentration of 1 ⁇ 10 -8 M to 1 ⁇ 10 -4 M was added to the Magnus tube cumulatively in such a dose that the distances between the logarithms of the amounts thereof added would be equal (1/2) until the maximum reaction of the heart rate increase was obtained. A curve showing the relationship between the dose of histamine and the reaction was thus obtained.
• the Magnus tube was washed several times and the atrium was stabilized for 30 min. Then, the above-mentioned process was repeated to obtain a curve showing the relationship between the dose of histamine and the reaction.
• the Magnus tube was washed several times and the atrium was stabilized for 30 min. Then, a test compound was placed in the Magnus tube. After 10 min, a curve showing a relationship between the dose of histamine and the reaction in the presence of the test compound was obtained.
• a PA 2 value of the test compound (negative number of logarithm of molar concentration of the test compound required for increasing the histamine concentration in the Magnus tube necessitated for causing a given reaction to 2-folds) was calculated from the second histamine dose/reaction curve and the third histamine dose/reaction curve obtained in the presence of the test compound by J. M. Van Rossum's method [Arch. int. Pharmacodyn., 143, 299 (1963)].
• H 2 -33 2-N- ⁇ 3-[3-(1-piperidinomethyl)phenoxy]-propyl ⁇ amino-5-methylamino-1,3,4-thiadiazole,
• TAS 2-N- ⁇ 3-[3-(1-piperidinomethyl)phenoxy]propyl ⁇ -amino-5-amino-1,3,4-thiadiazole hydrochloride.
• the stomach was taken out under etheral anesthesia and the gastric juice was taken out.
• the gastric juice was centrifuged. The quantity, acidity and pepsin activity of the supernatant liquid were determined.
• the acidity was determined by titration with 0.1N NaOH till pH 7.0 by means of a buret.
• the amount of the acid discharged per hour was calculated by multiplying the acidity by the quantity of the juice.
• Pepsin activity was determined by Anson's method [J. gen. Physiol. 21 79 (1938)].
• cimetidine was used as a comparative medicine.
• cimetidine and ranitidine were used as comparative medicines. The tests were effected using three standard doses of 6.7 mg/kg, 20 mg/kg and 60 mg/kg.
• test results of H 2 -33 are shown in Table 3. Those of H 2 -37 are shown in Table 4 and those of TAS are shown in Table 5.
• results of the tests of H 2 -33 and H 2 -37 are the averages of respective groups consisting of five rats.
• the results of the tests of TAS are the averages of the group consisting of ten rats.
• test results of TAS in doses of as small as 0.7 mg/kg, 2.2 mg/kg, 6.7 mg/kg and 20 mg/kg are shown in Table 6.
• Donryu rats weighing 200 to 230 g were used. Each group consisted of 6 rats. After fasting for 72 h, the rats were subjected to an abdominal operation under etheral anesthesia. The pylorus was ligated. Immediately thereafter, a given dose of a test sample was placed in the duodenum. Thereafter, neither food nor water was given. After 8 h, the stomach was taken out under etheral anesthesia and immersed in 1% formalin solution for 10 min. The stomach was cut along the greater curvature. The area of ulcer formed in the forestomach was determined by an anatomico-microscopic observation (magnification: ⁇ 10). The rate of control of the ulcer (%) was calculated as compared with a control. This test was effected according to the specification of Gastroenterology 4, (5), 43-61 (1945).
• test results are shown in Table 5. With 12.5 to 50 mg/kg of TAS, antiulcer effects far superior to those obtained by using 200 mg/kg of cimetidine or ranitidine were obtained.

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• Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
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• 1983
  • 1983-09-24 JP JP58175221A patent/JPS6067474A/ja active Granted
• 1984
  • 1984-07-10 CA CA000458538A patent/CA1248112A/en not_active Expired
  • 1984-07-16 GB GB08418085A patent/GB2146982B/en not_active Expired
  • 1984-07-18 DE DE3426533A patent/DE3426533A1/de active Granted
  • 1984-07-18 CH CH3496/84A patent/CH661514A5/fr not_active IP Right Cessation
  • 1984-07-19 US US06/632,333 patent/US4587254A/en not_active Expired - Fee Related
  • 1984-08-07 FR FR8412477A patent/FR2552433B1/fr not_active Expired

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